The Neuromuscular Junction( Neuromuscular Synapse )

Dr. Taha Sadig Ahmed

•Anterior Horn Cells

( Motor Neurons ).

•Motor Unit : is the

motor neuron

(Anterior horn Cell)

and all the muscle fibers it

supplies

Neuromuscular Junction (NMJ)

The Neuromuscular junction consists ofA/ Axon Terminal : contains

around 300,000 vesicles whichcontain the neurotransmitter

acetylcholine (Ach).B/ Synaptic Cleft:

20 – 30 nm ( nanometer ) spacebetween the axon terminal & the

muscle cell membrane. It contains

the enzyme cholinesterase whichcan destroy Ach.

C/ Synaptic Gutter ( Synaptic Trough)

It is the muscle cell membranewhich is in contact with the

nerve terminal . It has many folds called Subneural Clefts , which

greatly increase the surface area , allowing for accomodation of large

numbers of Ach receptors . Ach receptors are located here .

The Neuromuscular junction consists ofThe entire structure of axon

terminal , synaptic cleft and synaptic gutter is called “ Motor

End-Plate. ” Ach is synthesized locally in the

cytoplasm of the nerve terminal , from active acetate

(acetylcoenzyme A) and choline.

Then it is rapidly absorbed into the synaptic vesicles and

stored there .The synaptic vesicles

themselves are made by the Golgi Apparatus in the nerve

soma ( cell-body) .Then they are carried by

Axoplasmic Transport to the nerve terminal , which contains

around 300,000 vesicles .

Acetylcholine (1)Ach is synthesized locally in

the cytoplasm of the nerve terminal , from active acetate

(acetylcoenzyme A) and choline.

Then it is rapidly absorbed into the synaptic vesicles and

stored there .The synaptic vesicles

themselves are made by the Golgi Apparatus in the nerve

soma ( cell-body) .Then they are carried by

Axoplasmic Transport to the nerve terminal , which

contains around 300,000 vesicles .

Each vesicle is then filled with around 10,000 Ach

molecules.

Acetylcholine (2)•When a nerve impulse

reaches the nerve terminal,

•it opens calcium channels

calcium diffuses from the ECF int the axon

terminal Ca++ releases Ach from

vesicles by a process of EXOCYTOSIS

•One nerve impulse can release 125 Ach

vesicles. •The quantity of Ach

released by one nerve impulse is more than

enough to produce one End-Plate Potential.

Ach combines with its receptors in the subneural clefts. This opens sodium

channels & sodium diffuses into the muscle

causing a local,non-propagated potential called the “ End-Plate

Potential (EPP)”, whose value is 50 – 75 mV .

This EPP triggers a muscle AP which

spreads down inside the muscle to make it cntract.

•After ACh acts on the receptors , it is hydrolyzed by the enzyme Acetylcholinesterase (cholinesterase ) into

Acetate & Choline . The Choline is actively reabsorbed into the nerve terminal to be used again to form ACh.

This whole process of Ach release, action & destruction takes about 5-10 ms .

Myasthenia Gravis•Auto-immune disease

•Antibodies against Ach receptors destroy many of the receptors decreasing the EPP , or even preventing its

formation weakness or paralysis of muscles ) depending on the severity of the disease. (

patient may die because of paralysis of respiratory muscles .

•Treatment : Anti-cholinestersae drugs . These drugs inactivate the cholinesterase enzyme ( which destroys

Ach) and thereby allow relatively large amounts of Ach to accumulate and act on the remaining healthy receptors

good EPP is formed muscle contraction .

Drugs Acting on the NMJ

•Drugs that stimulate the muscle cell by Acetylcholine-like action : nicotine , methacholine , carbachol.

•Drugs that block neuromuscular transmission : Curare and curare-like drugs ( curariform drugs ) . They have a

chemical structure similar to ACh , but can not stimulate the receptors . They occupy acetylcholine receptors and

thereby prevent ACh from acting on its receptors muscle weakness or paralysis . Example : Tubocurarine. It is used

during some surgical operations. •Anticholinesterase drugs ( e.g. Neostigmine,Physostigmine)

Used in treatment of Myasthenia Gravis . These drugs inactivate the cholinesterase enzyme ( which destroys Ach)

and thereby allow relatively large amounts of Ach to accumulate and act on the remaining healthy receptors

good EPP is formed muscle contraction .

Muscle Physiology

The Muscle Action Potential

•Muscle RMP = -90 mV ( same as in nerves ). •Duration of AP = 1-5 ms ( longer duration than

nerve AP , which is usually about 1 ms ) .

•CV = 3-5 m/s ( slower than big nerves ).

Muscle Contraction There are 4 important muscle proteins:

A/ two contractile proteins that slide upon each other during contraction:

(1)Actin

(2)Myosin,

B/ And two regulatory proteins :

(1)Troponin excitatory to contraction

(2)Tropomyosin inhibitory to contraction

•Each muscle cell (fiber) is 10 -80 micrometer long & is covered by a cell-

membrane called Sarcolemma.

• Each cell contains between a few hundreds to a few thousands Myofibrils.

•Each Myofibril contains 3000 Actin filaments & 1500 Myosin filaments.

•Each myofibril is striated: consisting of dark bands (called A-bands) and

light (I-bands).

Muscle Structure (2)A-bands consist mainly of

Myosin & Actin ; while I-bands consist of Actin .The ends of Actin are

attached byZ-Discs(Z-lines ) .The part of the Myofibril lying

between two Z-discs is called Sarcomere . It is about 2

mcrometers . When contraction takes

place Actin & Myosin slide upon each other , & the

distance between two z-discs decreases : This is called

Sliding Filament Mechanism

Sliding Filament Mechanism: will be discussed later(

Actin Filament consists of Globular G-actin molecules that are attached together to form a chain.

Each two chains wind togetherاlike a double helix

Two F-Actin strands

Groove between the 2 F-actin strands

>Each G-Actin molecule has a binding site for Myosin head( called actin active sites ) > These active sites are covered and hidden from the Myosin head by the inhibitory protein Tropomyosin > When Troponin is activated by Ca++ it will move the Tropomyosin away from these sites and expose them for Myosin.> then myosin immediately gets attached to them .

> when the myosin head attaches to actin it forms a “ cross-bridge ”

The diagram of Guyton

Myosin (1)

•Each Myosin molecule has (1) Head (2) Hinge (joint ) and ( 3 ) Tail ; and each myosin head contains an ATP

binding site as well as ATP-ase enzyme.

Myosin (2)

•Each 200 myosin molecules aggregate to form a myosin filament , from the sides of which project

myosin heads in all directions.

•The EPP at the motor end-plate triggers a

muscle AP •The muscle AP spreads

down inside the muscle through the Transverse

Tubules ( T-tubules ) to reach the Sarcoplasmic

Reticulum (SR) . In the SR the muscle AP

opens calcium channels ) in the walls of the SR (

calcium passively flows out ( by concentration

gradient ) of the SR into muscle cytoplasm Ca+

+ combines with Troponin

The activated troponin pulls the inhibitory protein tropomyosin away from the myosin binding sites on actin and once these sites on Actin are exposed myosin heads quickly bind to them

This binding activates the enzyme ATPase in the Myosin Head it breaks down ATP releasing energy which is

used in the “Power Stroke ” to move the myosin head

The “ power stroke ” means tilting of the cross-bridge head ( myosin head ) and dragging ( pulling ) of actin filament

•Then , on order to release the head of Myosin from Actin , a new ATP is needed to come and

combine with the head of Myosin. •Q: What is Rigor Mortis? •Q: ATP is neede for 3 things : what are they? •Q: Is muscle relaxation a passive or active

process ? Why?

•Q: What happens to A-band and I-band during contraction?

•Q: Ca++ is needed in nerve & muscle : when and where?

Summary (1)(1)Muscle AP spreads through T-tubules(2)it reaches the sarcoplasmic reticulum where opens

its Ca++ channels calcium diffuses out of the sarcoplasmic reticulum into the cytoplasm increased

Ca++ concentration in the myofibrillar fluid. (3)Ca++ combines with Troponin , activating it (4)Troponin pulls away Tropomyosin (5)This uncovers the active sites in Actin for Myosin(6)Myosin combines with these sites (7)This causes breakdown of ATP and release of snergy

which will be used in Power Stroke(8)Myosin and Actin slide upon each other contraction (9)A new ATP comes and combines with the Myosin head

.This causes detachment of Myosin from Actin.

Summary (2)

•ATP is needed for 3 things:

•)1 (Power stroke.

•)2 (Detachment of myosin from actin active sites.

•)3 (Pumping C++ back into the Sarcoplasmic reticulum .